21-substituted 3-keto-delta4-pregnenes



United States Patent 3,173,931 ZI-SUBS'EETUTED 3-KE'1G-A -PREGNENES Edward W. Cantrell, Pearl River, N.Y., Ruddy Litteil, Rivervale, NJ and Seymour Bernstein, New City, N.Y., assignors to American (Iyauamid Cornpaiey, Stamford, Conn, a corporation of Maine No Drawing. Filed Get. 31, 1962, Ser. No. 234,555 6 @lairns. (Cl. 260-39145) This invention relates to new steroid compounds. More particularly, it relates to 2l-substituted E-Keto-M-pregnenes and method of preparing the same.

The novel steroids of the present invention may be illustrated by the following structural formula:

/R CH;O (CH2) RN g: .QQ

wherein R and R are lower flkyl radicals, n is an integer from 2 to 4; and mineral acid salts thereof. The mineral acid salts may be hydrochlorides, hydrobrornides, sulfates and the like.

The above tree steroids :are, in general, crystalline solids relatively insoluble in water but soluble in organic solvents such as lower alkyl alcohols, acetone, ethyl acetate, benzene, toluene, chloroform, ether, petroleum et er and the like. The mineral acid salts are soluble in Water.

The present compounds are prepared by heating, for example, 3,20 bisethylenedioxypregn-S-ene-11,8,17ot,21- triol with potassium t-butoxide in a solvent and subsequently with a compound of the formula:

Hal (CH ,N

\R' Hal wherein R and R are lower alkyl radicals, Hal is halogen and n is an integer from 2 to 4. The reaction mixture is heated to a temperature within the range of 80 to 120 C. for from two hours to 30 hours. The 3,20 bisethylenedioxy alkylated steroid is obtained by evaporation of the solvent and crystallization from a solvent such as aqueous methanol. The 3,20-ethylene ketal groups can be re moved by acid hydrolysis with, for example, aqueous sulfuric acid to produce the corresponding 3,20-diketo steroid. These latter steroids can be purified by methods Well known in the art.

The compounds of the present invention have been found to have ianti-cholesteremic activity. They are therefore useful in lowering abnormally high blood cholesterol often present in certain cardiac conditions.

The followin. examples describe in detail the preparation of representative 21-suostituted S-lcetO-A -pregnenes.

2 EXAMPLE 1 Preparation f 3,20-bisethylenedioxy-21- (fi-diethylaminoethoxy)-pregn-5-ene-11;8,17a-ai0l A solution containing g. of 3,20-bisethylenedioxypregn 5 ene llfl,l7oc,21 triol and 8 g. of potassium tbutoxide in 400 ml. of dry dioxane is heated to reflux for one-halt hour. Diethylaminoethyl chloride hydrochloride (6 g.) is added and heating is continued for twenty hours. A second portion of alkylating agent (10 g.) is added. The reaction mixture is refluxed an additional five hours, cooled and filtered. The filtrate is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and evaporated to give 8 g. of pasty crystals. Crys tallization from methanol-water gives 4.8 g., melting point 110-1l2 C. A sample for analysis is crystallized once from methanol-Water and once from =acetone-petroleum ether and has melting point 118-120 C, [aJ 33.

In the above example when dimethylaminoethyl chlo ride hydrochloride, 3-diethylaminopropyl chloride hydrochloride and 4-diethylaminobutyl chloride hydrochloride are substituted for diethylaminoethyl chloride hydrochloride, 3,20-bisethylenedioxy-21-( ,B-dimethylaminoethoxy) pregn-S-ene-1 1,8, l7cc-(il0l; 3,20-bisethylenedioXy-21-('y-diethylaminopropoxy)-pregn-5-ene-11B,?l7u-di01 and 3,20- bisethylenedioxy 21 (B-diethylaminobutoay)-pregn-5- one-11,8,1'l'a-diol, respectively, are produced.

EXAMPLE 2 Preparation of 116,17a-dihydr0xy-2l-(B-dietkylaminoethoxy -pregn-4-ene-3,20-dioize A solution of 1.25 g. of 3,20-bisethylenediox -2l-(fi-diethylaminoethoxy)-pregn-5-ene-115,17a-diol in 50 ml. of ethanol and ml. of 8% sulfuric acid is heated to reflux for one and one-half hours. T he solution is concentrated to about ml, neutralized with 20% sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with Water and saturated sodium chloride solution, dried and evaporated. The residue is crystallized from acetone to give 710 mg., melting point 161162 0., A 242 mu (617,200); [ab +116".

When in the above example 3,20-bisethylenedioxy-21- (B diethylaminoethoxy) pregn 5 ene 1113,1704 dial is replaced with 3,20 bisethylenedioxy 21 (,B-dimethylaminoethoxy) pregn 5 ene 1113,17! diol; 3,20-bisethylenedioxy 21 (v-diethylamhiopropoxy) pregn 5- ene 115,170 diol and 3,20-bisethylenedioxy-21-(5-di ethylaminobutoxy) pregn 5 ene 11,13,170: diol the product resulting is respectively 11fi,l7ci-dihydroxy-21- (fi-dirnethylaminoethoxy) pregn 4 ene 3,20 dione; 116,17 dihydroxy 21 (6 diethylaminopropoxy)- pregn 4 ene 3,20 dione and 11fl,17 x-dihydro :y-2l- (ii-diethylaminobutoxy)-pregn-4-ene3,20-dione.

EXAMPLE 3 Preparation 0 115,1 7e-dihydr0xy-2Z (/B-diethylaminoezhoxy -pregn-4 -ene-3,20-di one hydrochloride A solution of 115,17a-dihydroXy-21-(fi-diethylaminoethoxy)-pregn-4-ene-3,20-dione in diethyl ether is treated with hydrogen chloride to give the product of the example.

3 4 We claim: wherein R and R are lower alkyl radicals, n is an integer 1. A compound selected from the group consisting of: from 2 to 4 and its mineral acid salts.

CH 2. The compound 115,170 dihydroxy 21 (fl-diethyl- R aminoethoxy) -pregn-4-ene-3 ,ZO-dione. OHPO (OH) 5 3. The compound 11 B,17a-dihydroxy21-(,B-dimethylammoethoxy) -pregn-4-ene-3 ,20-d1one. I :0 4. The compound 113,17Zx dihydroxy 21 (v-diethylaminopropoxy -pregn-4-ene-3 ,ZO-dione. HO 5. The compound 115,170 dihydroxy 21 (ii-diethyl- CH3 1O aminobutoxy)-pregn-4-ene-3,20-dione.

6. The compound 116,170; dihydroxy 21 (,B-diethylaminoethoxy)-pregn4-ene3,20-dione hydrochloride.

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 